Manufacture of esters of 2-phenyl-quinoline-4-carboxylic acid



' carboxylic acids, mentioned above.

Patented July 28, 1931 0 -f UNI T D STATES PATENT OFFICE ALBERT Boson, or BRUNSWICK,

GERMANY, ASSIGNOR TO JOHANN A. WfiLFING, OF BERLIN, GERMANY NMANUFACTURE or ns'rERs or Z-PHENYL-QUINOLINE-IL-CARBOXYLIC ACID Ito Drawing.

10 means tasteless and have still a somewhat bit terand-disagreeable taste (see Frankel, Arzeneimittelsynthese 1927 page 83i' section 8), thus showing no'ad-Vantage over the corresponding free acids. e

Now, I have foundthat in the ester-series which 2-phenylquinoline-t-carboxylic acid and its homologues in which the benzene nucleus is alkylsubstituted 00011 c ioon coon 1 m I, m (1N cant v N .0 3; p N can;

I i i I Y i Ha form with primary alcohols of the fatty series, n-propylesters are the first of this series which form entirely tasteless esters. Then follow n-butyL and iso-butylester which are also quite tasteless and show the same therapeutical action, as the corresponding free In Patent No. 1,502,275, page 1, l'nes 29-35, of the esters of 2-phenylquinoline-t-carboxylic 1 acid vn-propylesters melting at 56-57 C. are mentioned. as intermediate products for the formation of the corresponding hydriodides, and in Patent No. 1,552,568, page 1, lines 14:27, are mentioned n-propyland n-butyl esterof 6-methyl-2 -phenylquinoline-4- carboxylic acid of the melting points 82 C. and 64 C. respectively alsoasintermediate products for the formation of the corresponding halogen-acid compounds, but the methods fortheir production which are disclosed in said patents are technically too expensive and not very feasible. According to the examples recited in said patents, the esters are prepared either by boiling 2-phenylquinolinel-carboxlyic acid or 6-methyl-2-phenylquinoline-" Application filed March 9,

1928. Serial No. 260,550.

4-carboxylic acid with an excess of the corresponding anhydrous alcohol in the presence ofa current of dry hydrochloric acid gas, or by producing the acid-chloride of the acid and causing this to react with the anhydrous alcohol corresponding to the desired ester. The other known methods for esterification of organic carbonic acids as described in British Patents No. 150,401 and 167,066 and in Patents N 0. 1,336,952 and 1,878,343 for the production of alkyland aralkylesters, such as allyland benzylesters of 2-phenylquinoline eL-carboxylic acid, which consist in causing alkyl-halides to react on the sodium salt of 2-phenylquinoline--carboxylic acid are likewise not well suitable for producing the npropyl-, n-butyland iso-butylesters of 2- phenylquinoline-4 carboxylic acid and its homologues in which the benzene nucleus is alkylsubstituted, as those alkyl halides are too expensive for technical use.

The known method proposed by Emil Fischer for the production of esters of carboXylic acids (Berichte der deutschen chem. Gesell. vol. 28 page 3252) by boiling the carboxylic acids for four hours and longer with an excess of the alcohols corresponding to the desired esters and containing up to 10% of concentrated sulfuric acid in proportion to the alcohol used, is not feasible, when n-propyl'-, n-butyland iso-butyl-esters of the carboxylic acids mentioned above are to be produced, because those quinoline-carboxylic acids form sulphates with sulfuric acid which are insoluble in the boiling alcohols and thus prevent esterification.

Now, I have found that n-propyl-, n-butyland iso-butylesters of 2-phenylquinoline-tcarboxylic acid and its homologues viz. 6- niethyl-2-phenylquinoline-4;-carboxylic acid and 6-8- dimethyl-2-phenylquino1ine-4=-carboxylic acid are readily and cheaply formed in great purity, when these carboxylic acids are treated with a threeor four-fold quantity of n-propyl-, n-butylor iso-butyl-hy-, drogen sulphate at a suitable temperature. This new method for esterification can be performed in open vessels at temperatures not exceeding 105 C., and it is finished I ification takes have sh W11, all;

ing temperatures are for several hours avoided, Very pure esters. This method foresterplace accordlng to the following equatlonsz Alk.OH+HzSO =A]k HSO4-{Hz0 Al1 .HSO4+R.OOOH =R;COO Allr.+H2SO4. A The n ono allzyiesuliuric acids are obtained by mixing equivalent quantities of pure anhydrous n-propyl-, n-loutyland lso-butyl alcohol and-concentrated sulfuric acid of de:

grees Be. which react upon each other evolution of great heat, To four parts by weight of'each alkyl-sullnric acid, thus produced, for'instance one part by weight of the, dry carboxylic acidsis mixed at 608(l C. andthe temperature is then'raised within half an hoin up to 1009* 105 C. The mixture is then cooled down and precipitatedin cold water; The estersseparate as yellowish oils whieh become crystalline after some time, some cases after .12-2 i ou 0 ltwas nettobe expect h t 2-pheny qilineli earhcxylic acid ancts om -z gi s, Whic form ulph i ur c' cid, ns luble in. hot, p opyl'andj buty a co ho g enld sci r adily and at s low a e pe mQliSSQiVsiH 11 116?alky i ifur aci n pure esters, w hile,,. as has been mentioned above, esters are not formed or very:

neemple iely t med, w n the carbonyl- 6: acids are boiled Withan ecesso-f theabove almholsiand a mallquanti y' f su u c acid, suc as; mi Fischer and-Spe (Ber-ich e der deutschen ch m vol. .28- page 3252'). pr s ribe. Qnthe other hand-these authors mention the fact thatthe methods for esteri ation are not to. generalized, but hat e rbexy'liciaoid reqnifres a definite niethe l-.-i lioren m pr ma y alcohols cnly react. 0,11; carboxylie acids fo ming e ter-s,

v Ewamplel To 80 parts'of n-propyl sulfuric acid,v ob tajned by addition of parts of anhydrous li-pr pylalqohol" to parts o concentrated sulfuric cid ("66' degrees; Be), are mixed 20 parts. of 2-phenylquinolinerl-carboxylic acid, WhiletheiniXture is] heated to. .6080 O, The temp. .rat is then a ed/to lQj0 l0-5,?

; so low. a temperature C. Within half an hour. After cooling the reaction mass is mixedwith 750 parts of cold water. The ester separates as a pale yellow oil which becomes crystalline after 12-24: hours. The crystalline mass is then filtered off, washed with cold water and recrystallized rorn niethylalcohol or any otheri'ndifferent organic solvent. vThe n-propylester of 2- phenylqiiinoline--'carlooxylic acid forms white needles melting at 63-64-: G. It is al most insoluble in water, but soluble in gastric juice. WVithmineral acids, such as hydrochloric acid; or sulfuric acid the ester forms salts which decompose and are split up. with much water into ester and freeacid.

" mane/p le by the addition or" 37 parts of anhydrous nebutylalcohol to. 50 parts of concentrated sulfuric acid (6.6 degrees B.), are mixed-20 parts of 2 phenylquinolineea carboxylic acid;

' while the mixtnre is heated 13060 Thefteniperature is, then raised to (1 within halfan hour. After cooling, the

reaction mass is mixed with .750 "partsof;

waterand the separating light yellow oil ale lowed tobecorne crystalline. After 24;:l1ours;

the crystalline mass is filteredlofi washed Withcold Water and the water pressed off. ZQhe raw ester is recrystallized fro-mg nethyl; alcohol, n-butylalcohol or: other indifi'erent organic solvent. Then-bntylester of 2-phenylq uinoline-4c-carhoxylic acid "forms white needles, rneltingat569-5Z Example 8 7, parts of isosbutyl-sulfuricacid, pro;

duced by the addition of 37 parts of anhydrous iso lo'utylalcohol to 50 parts of concen 87 partsof n-bntyl-sulfuric acid, obtained;

trate'd sulfuric acid (66 vdegrees B6), are v mixed with parts of Q-phenylquinoline-lcarboxylic whilfetl i e niixtur-e'is heated to GO -80 C. Y The'ternperature is thenraisec to l00-l05.C. within half an hour; After coolingthe reaction mass is mixed with 750 parts of cold water. I Theester separates as a pale yellow oil which becomes solid and crystalline; After 2 l'he'urs the crystalline mass is filtered ofi', washed with'cold water,

and pressed to remove the water. The isobutylester of 2-p-henylquinolinel-carboxylic' acid forms prismatic needles, melting at 39' 40 (1, when recrystallized froin' diluted inethylaleohol or isohutylalcohel.

6 methyl -Q-phenylqHinolineA carboxylic acid of the meltinglpoint of 228 C. hasfirst been ohta-ined lay Do'bn'er and 'Gieseclre (An nalen der' Chennie Vol. 242 page 296) from toluidine, benzaldehyde and pyruvic acid in an absolute alcoholic solution r V G7HBN -lorHioa 01110 CnHxqNOg 2 E20 H2,

It can produced much better by treating 5- 1rrethyliSatine (melting point 183 and cm 00 om (li 1 o v E N can acetophenone in a concentrated solution of caustic alkali at 90100 C.

coon

CuHs

The n-propylester of 6-methyl-2-phenylquinolinel-carboxylic acid is obtained from the free acid and n-propylsulfuric acid as described in Example 1. From methylalcohol recrystallized it shows hard needles melting at 7980 C.

e The n-butylester of 6-methyl-2-phenylquinolinel-carboxylic acid is obtained, as described in Example 2, from the free acid and n-butylsulfuric acid. Recrystallized from methylalcohol', it forms hard needles melting at 6i65 C. i

The new iso-butylester of 6-methyl-2-phenylquinolineAc-carboxylic acid obtained, as

shown in Example 3, from the free acid and iso-butyl-sulfuric acid forms, when recrystallized from methylalcohol, fine pale yellow needles melting at 74:75 C.

Contrary to the free 6-methyl-2sphenylqui- "nolinet carboxylic acid which is of a bitter and peppery taste, its n-propyl-, n-butyland isobutyl-esters are absolutely tasteless.

The new i 6-8-dimethyl-2-phenylquinolinel-carboxylic acid of the melting point of 284-235 C. can be obtained from 5-7-dimethylisatine (melting point 238 C.) and acetophenone in the presence of caustic alkali solution at 90100 C.

From the alkaline solution of this melt in a large quantity of water, the free acid is precipitated by diluted hydrochloric acid. When recrystallized from much methylalcohol, the 6-8-dimethyl-2-phenylquinoline-4 carboxylic acid forms small grey crystals melting at 234235 G. Like the lower homologues, the 6-8-dimethyl-2-phenylquinoline-4-carboxylic acid is of a bitter and peppery taste, while the following n-propyl-, n-butyland isobutylesters of this acid are quite tasteless.

The newn-propylester of 6-8'dimethyl-2- phenylquinoline-a-carboxylic acid can be ob tained as described inExamplel from the free 60-80 G. and ending after half an hour at 100105 C. The reaction mass is treated as described in Example 2. lVhen recrystallized from methylalcohol, the new n-butylester form(sj almost colourless needles melting at 80 The new iso-butylester of 6-8-dimethyl-2- phenylquinoline-a-carboxylic acid, obtained from th-elatter acid and iso-butyl-sulfuric acid as shown in example 3, forms, when recrystallizedfrom methylalcohol, pale yellow needles melting at 83 C. y

I claim:

1. The process of manufacturing a compound represented by the following structural formula ooox O 00H: N

in which X represents the n-propyl-, n-butyl and iso-butyl-radical, Y and Z a hydrogen atom, or the methyl radical, which process comprises causing the mono-X-H sulfate, in which X represents the n-propy1-, n-butyland iso-butyl-radical to react on carboxylicacids of the above formula at a suitable temperature, substantially as described.

2. A chemical compound, represented by the following structural formula COOX CaH: CH3 N in which X represents the n-propyl, n-butyland iso-butyl-radical.

In testimony whereof I hereunto afiix my signature.

ALBERT BUSCH.

acid by treating the same with n-propyLsulfurio acid at -105 C. for about half an hour. 20 parts of 6-8-dimethyl-2-phenylquinoline--carboxylic acid are mixed with 80 parts of n-propyl-sulfuric acid, obtained by the mixing of 30 parts of anhydrous n-propylalcohol and 50 parts of concentrated sulfuric acid at 6080 G. The temperature is then 

